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© 1999 American Society for Clinical Oncology Quality of Life and Performance in Advanced Head and Neck Cancer Patients on Concomitant Chemoradiotherapy: A Prospective ExaminationFrom the Departments of Medicine, Radiation and Cellular Oncology, Department of Health Studies, and Surgery, the Chicago Cancer Research Center, University of Chicago, Chicago; and Department of Medicine, Northwestern University, Evanston, IL. Address reprint requests to Marcy A. List, PhD, Associate Director, Cancer Control and Community Research, University of Chicago Cancer Research Center, 5841 S Maryland MC 1140, Chicago, IL 60637; email malist{at}mcis.bsd.uchicago.edu
PURPOSE: To prospectively evaluate performance and quality of life (QOL) in advanced-stage head and neck cancer (HNC) patients on a curative-intent, concomitant-chemoradiotherapy (CT/XRT) (twice-daily radiation, fluorouracil, hydroxyurea, and cisplatin) regimen aimed at improving locoregional control, survival, and QOL. PATIENTS AND METHODS: Sixty-four patients were assessed before, during, and at 3-month intervals after treatment. Standardized measures of QOL (Functional Assessment of Cancer Therapy–Head and Neck), performance (Performance Status Scale for Head and Neck Cancer Patients and Karnofsky Performance Status Rating Scale), and patient-reported symptoms (McMaster University Head and Neck Radiotherapy Questionnaire) were administered. RESULTS: Acute treatment toxicities were severe, with declines in virtually all QOL and functional domains. Marked improvement was seen by 12 months; general functional and physical measures returned to baseline levels of good to excellent. Although up to a third of the patients continued to report problems with swallowing, hoarseness, and mouth pain, these difficulties were present in similar magnitudes before treatment. The following symptoms were more frequent at 12 months: dry mouth (58% v 17%), difficulties tasting (32% v 8%), and soft food diet (82% v 42%). Twelve-month diet was not related to pretreatment functioning, disease, treatment, or patient characteristics. Twelve-month QOL was best predicted by pretreatment QOL, with very little relationship to residual side effects or functional impairments. Small numbers of patients in four of the five disease sites precluded examination of outcome by site. CONCLUSION: These data support the feasibility of intense CT/XRT as primary treatment for advanced HNC. Results confirm acute toxicity but indicate that many of the treatment-related performance and QOL declines resolve by 12 months. The persistent inability to eat a full range of foods warrants further attention and monitoring.
HEAD AND NECK cancer (HNC) remains a considerable challenge to both patients and health care providers. Of approximately 40,000 new cases diagnosed annually,1 the majority present with locoregionally advanced disease (stage III or IV).2 Traditional aggressive treatment, surgery followed by radiotherapy, often results in functional and psychosocial dysfunction, yet still cures only a minority of patients. Over the past three decades, investigations have explored the addition of chemotherapy, either as induction (neoadjuvant), adjuvant, or concomitant with radiation treatments.2 The goal of these regimens is to improve disease control, survival, and quality of life (QOL) through the preservation of function.2-4 Recent studies evaluating concomitant chemoradiotherapy (CT/XRT) regimens suggest small but statistically significant improvements in both disease-free and overall survival.5-14 In addition, these regimens offer curative intent to patients with unresectable tumors15 and thus are encouraging in terms of disease-related outcomes. Evaluation of HNC treatment outcome, however, must also include QOL and functional end points as well as disease control. Studies of patients treated with traditional surgery with or without radiation therapy have documented significant and extensive impairment, including disfigurement, speech disorder, dry mouth, stiffening/constriction of local tissues, chewing and swallowing dysfunction,16-23 mood disturbance, anxiety, and depression.16,17,24-27 Greater and more persistent disturbance has been associated with surgery and radiotherapy when compared with radiotherapy alone.16,17,22,28,29 There are considerably fewer QOL and performance data on the more recently developed CT/XRT regimens. Early data, however, suggest that by minimizing surgery, these treatments generally reduce the occurrence of severe cosmetic impairment and certain functional deficits, specifically speech.30,31 On the other hand, these advantages are not achieved without other costs to the patient, in particular, heightened treatment toxicity. The high total radiation dose administered in the context of chemoradiosensitizers is associated with an increase in acute toxicity, including severe mucositis, neutropenia, and thrombocytopenia.32 The late effects of these toxicities and long-term medical and/or physical problems, although currently under investigation, have not yet been well documented. Furthermore, little is known about patients' perceptions of treatment toxicity, residual impairments, and their impact on patient-rated QOL.30 Ideally, comparisons between patients treated with primary surgery and those treated with primary CT/XRT should be collected in the context of randomized clinical trials. In the absence of such trials, however, systematic longitudinal documentation of QOL and functional outcome in patients undergoing defined treatment protocols is essential. At the University of Chicago (U of C), HNC clinical trials have focused on intensification of CT/XRT regimens with the goal of further increasing disease control and survival while preserving function. This article focuses on a hyperfractionated radiation therapy (XRT) regimen that was designed with the specific aim of improving locoregional control. The regimen, closed to accrual in January 1996, consisted of five cycles of concurrent CT/XRT with fluorouracil, hydroxyurea, twice-daily (BID) radiation, and cisplatin cycles 1, 3, and 5. Primary study end points include survival and locoregional and distant control. Given the intensity of the treatment, however, it was expected to be associated with numerous and severe acute toxicities and possibly an increase in chronic toxicity. To determine, from the patients' perspective, whether these toxicities might offset increases in survival, the assessment of functional, performance, and patient QOL outcomes were integral components of the trial. This article presents longitudinal QOL and performance data using measures reflecting patients' perception of performance, symptoms, side effects, and QOL. The study was designed to answer the following questions: (a) What is the effect of acute treatment toxicities on patients' immediate (ie, on-treatment) QOL, performance and functional status, and experience and report of symptoms and side effects? (b) What is the pattern and extent of patients' recovery over the 12 months following treatment? (c) What are the more chronic (12-month) effects of disease and treatment on patients' performance and functional status, report of symptoms, and QOL? (d) Which, if any, baseline (pretreatment) variables (patient characteristics, disease or treatment parameters, performance, or symptoms) are associated with poorer 12-month performance and QOL.
Eligibility Participants in the QOL companion study included all U of C and Northwestern University (NU) patients enrolled onto the designated joint U of C/NU intensive BID CT/XRT regimen.32 Treatment protocol eligibility criteria included stage III (base of tongue, pyriform sinus) or IV (all disease sites) HNC, no prior chemotherapy, XRT or primary surgical treatment, and no distant metastasis. Patients received five cycles of concomitant CT/XRT as follows: cisplatin 100 mg/m2 on day 1, fluorouracil 800 mg/m2 as continuous infusion over 120 hours (days 1 through 5), hydroxyurea 1 g orally every 12 hours for 11 doses on days 0 through 5, and concomitant XRT at 1.5 Gy administered BID on days 1 through 5 (15 Gy; total XRT dose, 75 Gy). Patients were hospitalized during the 5 days of treatment, which was followed by a 9-day rest period during which the patients received granulocyte colony-stimulating factor. In general, surgery was reserved for residual disease at the primary site or neck dissection after completion of CT/XRT.
Assessment Procedures The following assessment tools were used: (a) The Karnofsky Performance Status Rating Scale describes global functioning in terms of mobility and ability to maintain employment, live at home, and care for oneself. The PC rated the scale after discussion with the patient; ratings are in deciles from 0 to 100, with higher scores indicating better performance.33 (b) The Performance Status Scale for Head and Neck Cancer Patients (PSS-HN) consists of three subscales: Normalcy of Diet, Understandability of Speech, and Eating in Public. The interviewer rates the patient on each subscale based on the patient's responses to targeted questions. Scores on each subscale range from 0 to 100, with higher scores indicating better performance. The PSS-HN has good interrater reliability and ability to discriminate levels of functioning across the broad spectrum of HNC.20,34,35 (c) Selected questions from the McMaster University Head and Neck Radiotherapy Questionnaire were used to assess patients' experience of radiation-related side effects (eg, dry mouth, throat pain, and skin irritation). Patients rate each symptom on a 7-point Likert-type scale, with 1 indicating that a given item is "a great deal" of trouble and 7 indicating that the item is "not at all" troublesome. The questionnaire has proven sensitive to treatment effects and correlates highly with existing measures of toxicity and performance ratings.36 (d) The Functional Assessment of Cancer Therapy–Head and Neck (FACT-H&N), a cancer-specific QOL instrument, consists of a 33-item core to which an 11-item site-specific, Head and Neck (H&N) subscale is added (version 2).37,38 The measure is completed by the patient and yields a global QOL score (FACT-G; range, 0 to 120 points) and six subscale scores covering the following domains: Physical (0 to 28), Social (0 to 28), Relationship with Doctor (0 to 8), Emotional (0 to 20), Functional (0 to 28), and H&N Concerns (0 to 44).
Statistical Methods Change over time was examined by plotting the mean score for each outcome variable versus time. Pearson correlations were used to summarize the relationship between scores at different time points. Treatment effects (defined as mean change from baseline to end of treatment) and recovery (defined as mean change from on-treatment to 12 months) were evaluated using paired t tests. Because this analysis of recovery excludes patients with missing 9- and 12-month scores, a linear random-effects model39 (using the unweighted least-squares estimate) was fit for each item, using all patients41-43 with at least two posttreatment measurements. This model assumes that each patient's posttreatment scores follow a linear regression with random intercept and slope; visual inspection of the individual profiles confirmed the adequacy of this assumption. This model yielded estimates of recovery very similar to the simple mean differences described above. Both 12-month global QOL and normalcy of diet were regressed on baseline characteristics, radiation dose, and a subset of 12-month outcome variables. All-subsets regression was performed using Mallows' Cp40 to identify the best predictive model(s). The usual diagnostic plots were then used to examine the adequacy of the final model. Although disease site was included as a covariate, the small number of patients (eight or fewer) in four of the five disease sites provides little power to detect between-site differences.
Patient Characteristics A total of 64 U of C and NU patients were enrolled onto the treatment protocol, and 46 patients were alive at 12 months after completion of therapy. Participants represented an ethnically diverse group of 47 men and 17 women. Median age was 55 years (range, 16 to 81 years), 63% had at least a high school education, 49% were married, 56% had incomes of less than $30,000, and 63% reported that they were working before their cancer diagnosis. Approximately two thirds of the sample reported a history of moderate to heavy alcohol intake (> two drinks per day), and approximately half reported more than a 20 pack year history of cigarette smoking. As designated by the treatment protocol, patients had stage IV or poor-prognosis stage III (four patients) nonmetastatic disease; they represented a range of disease sites, with the three most frequent sites being the oropharynx (52%), larynx (15%), and hypopharynx (17%). Selected patient characteristics are listed in Table 1.
Of the 46 patients alive at 12 months, 36 had had no surgery other than a biopsy with or without neck dissection. Three additional patients had small laser excisions before CT/XRT. Of the remaining seven patients, four had organ-preserving surgical resections at the primary site before CT/XRT and three had surgery after CT/XRT for residual disease.
Pretreatment Data
There were no statistically significant pretreatment differences between the 46 patients who were alive at 12 months and those who died within 12 months (n = 18) on any of the above measures.
Acute Treatment Effects For performance parameters and symptoms (including the H&N concerns subscale of the FACT-H&N), pretreatment scores were generally not predictive of on-treatment scores (correlation coefficients ranged from -.12 to .39). In contrast, global pretreatment QOL was moderately predictive of on-treatment scores (r = .62), as were individual QOL dimensions (ie, correlation coefficients for subscales ranged from .32 to .64).
Recovery
Plots of mean scores over time together with formal statistical comparisons (Table 3) suggested the following four basic patterns of decline (from baseline) and recovery (over 12 months) (Fig 1):
(a) A decline on-treatment with gradual improvement to, or approaching, pretreatment levels, and no clinically relevant difference between baseline and 12-month values (throat and mouth pain, swallowing, skin problems [itching, pain], hoarseness, Functional and Physical well-being, overall QOL [FACT-G] and global performance status [Karnofsky]). This pattern of recovery was the most common. Observed declines on Karnofsky and skin itching were judged not to be clinically relevant41; (b) A decline on-treatment with only limited recovery over time and both statistically and clinically significant differences between pretreatment and 12-month scores (Normalcy of Diet, sticky saliva, Eating in Public, and the H&N Concerns subscale); (c) A decline on-treatment with no statistically or clinically significant improvement over time (dry mouth, difficulties tasting); and (d) Little or no decline on-treatment and no clinically relevant change from baseline to 1 year (Speech, chewing, Emotional and Social well-being, and Relationship with Doctor). Plots of individual scores over time revealed enormous variability. For instance, for some symptoms, 25% to 50% of the sample reported no difficulty (eg, 6 or 7 on 7-point Likert scale) at any time. Whether this finding represents a reporting artifact, disinterest on the part of the patient, or a true lack of symptoms is unknown.
Predictors of 12-Month Functioning
Variables Associated With 12-Month Global QOL Regression analyses were also used to determine whether there were specific 12-month outcomes (Karnofsky, PSS-HN) or residual symptoms (10 McMaster items). The best-fitting model, shown in Table 4, accounts for 76% of the variation in 12-month FACT-G. This model indicates that after accounting for baseline QOL (FACT-G), higher scores (better performance) on hoarse voice, mouth pain, Speech, and Eating in Public were all associated with higher 12-month QOL.
Variables Associated With 12-Month Diet In particular, disease site was not associated with outcome diet, controlling for baseline diet (P = .353). On the other hand, three 12-month outcomes (swallowing, Eating in Public, and Understandability of Speech) had statistically significant positive correlations with Normalcy of Diet and together accounted for 56% of the variation in 12-month Diet (n = 36).
Alcohol Consumption and Tobacco Use
Aggressive concomitant CT/XRT regimens lead to high locoregional control and increased survival, as well as allow for organ preservation.6 By minimizing surgery, they reduce the likelihood of potential negative cosmetic sequelae as well as certain functional impairments. On the other hand, they impose severe acute toxicities and likely some degree of chronic impairment. This study represents one of the first examinations of patients' experience of an intensive, cisplatin-based CT/XRT protocol, and findings support its feasibility in terms of QOL and general performance outcomes. As anticipated, while on treatment, patients' performance and functional status declined dramatically with a corresponding increase in symptoms. By 12 months after treatment, however, there was improvement in most domains and recovery to, or approaching, pretreatment levels in many areas. Patients showed few limitations in general day-to-day activities, including speech. Although up to a third continued to report that swallowing, hoarseness, and mouth pain were troublesome, these difficulties were present in similar magnitudes before treatment. The most salient persistent difficulties included dry mouth, tasting, sticky saliva, comfort in eating/socializing with others, and ability to eat a full range of solid foods. Several of these outcomes (hoarseness, mouth pain, Speech, and Eating in Public) were associated with overall QOL at 1 year. These residual effects are not unique to intensive concomitant CX/XRT but are well-documented effects of XRT, alone or after surgery, for treatment of HNC.42,43 Dry mouth and loss of taste have also been shown to persist and even worsen over time.44,45 The finding that 82% of patients restricted their diets to soft foods is relatively consistent with other descriptions of the functioning of HNC patients after treatment. For example, studies have reported such dietary restrictions after surgery plus radiation therapy in up to 69% of oral and pharyngeal patients46 and 58% of intraoral patients42; in a group of advanced-stage base-of-tongue cancer patients, the mean Normalcy of Diet score was 32.28 In a sample of back-of-tongue cancer patients at least 3 years from completion of primary radiotherapy, 65% had diets restricted to soft foods.45 In general, comparison across studies is difficult; many reports include both early- and late-stage patients at various times after treatment, and data are presented in terms of mean scores on a variety of measures. Twelve-month diet was not related to any of the baseline characteristics in the current sample. However, as the relatively small sample size provided little power to detect between-site differences, primary tumor site and its related structural and/or associated radiation-field damage cannot be ruled out as factors affecting diet outcome. Patterns of alcohol consumption and tobacco use during and after treatment have been associated with both survival and symptom dysfunction47 and may also be related to diet outcome. Unfortunately, data in the current study were insufficient to permit examination of this issue. Finally, although data from ongoing investigations suggest little relationship between outcome diet and dentition, more formal assessment of dentition is needed. Interpreting QOL scores in the context of baseline values suggests that with the exception of the H&N Concerns subscale assessing specific HNC symptoms, patients have adapted well; that is, all other dimensions had returned to pretreatment levels by 12 months. There was remarkably little change in social and emotional indices, which suggests that patients' sense of psychologic well-being was relatively independent of treatment toxicity and its imposed functional limitations. It is difficult to interpret the absolute value of FACT-H&N scores. However, subscale scores and SDs from the current sample were well within the range of those obtained from a large sample of diverse cancer patients used for instrument validation.37 The stability of QOL and its lack of relation to disease parameters, performance status, or patient demographics are consistent with our previous work20,34,35 as well as that of other investigators studying HNC patients.23,48,49 The data presented here have a number of clinical applications. First, they can be used by clinicians to educate and prepare patients for the effects of their treatment, both the acute declines as well as possible patterns of recovery. Second, the data point to a number of areas for possible intervention. In general, one might take two complementary approaches to early intervention, targeting either the subgroup of patients identified as "at risk" for a poorer outcome or those residual symptoms that remain problematic for a majority of patients. Since baseline QOL was predictive of 12-month QOL, pretreatment screening may be used to identify patients in need of special monitoring. On the other hand, although pretreatment performance or symptomatology was not found to predict posttreatment functioning, the data highlight specific persistent problems worthy of further attention. For example, areas in which patients show no recovery (eg, difficulties tasting, dry mouth) and those for which poorer functioning is associated with poorer overall outcome QOL (eg, hoarseness, mouth pain, Speech, and Eating in Public) might reasonably be selected as targets for intervention. The authors suggest that early interventions designed to minimize these residual symptoms and functional impairments are indicated and once demonstrated as feasible, should be offered to all patients. Study findings confirm the importance of the patient's perspective in evaluating aggressive CT/XRT regimens, ie, that the subjective experience of specific symptoms varies and is not consistently associated with functional outcome. In addition, the data suggest a number of areas for more detailed examination in the next series of investigations. More complete smoking and alcohol-use data should be collected and its influence on functional and QOL outcomes explored. Larger study cohorts would permit a more powerful comparison of performance outcome across disease sites. Finally, from a mechanistic, objective perspective, comprehensive barium swallowing-function tests and construction and integration of the contribution of specific radiation fields would also likely improve understanding of these outcomes.
Supported in part by NCI Cancer Center Support grant no. CA 14599 and NCI Oral Cancer Center "Carcinogenesis and Novel Therapeutics in Oral Cancer" grant no. DE/CA11921.
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ABSTRACT
INTRODUCTION
